We have previously described that HIV-1 gp120 binds to and signals through the integrin alpha4beta7, the gut-homing receptor. In a follow up study, we demonstrated that alpha4beta7high CD4+ T cells represent a target cell that is particularly susceptible to HIV-1 infection. We have also found that alpha4beta7 appears in a complex with CD4 and that alpha4beta7high CD4+ T cells are CCR5high and CXCR4low. These latter findings may in part provide an explanation for the bias towards the selective transmission of CCR5 utilizing viruses (R5). Consistent with a possible role for this interaction at transmission is the finding that alpha4beta7high CD4+ T cells are found in the genital mucosa. We hypothesize that alpha4beta7-gp120s interactions play a role in both transmission and HIV-mediated immune dysfunction. We have analyzed several HIV gp120s from early transmitting viruses (founder viruses) and observed that these gp120s have an increased affinity for alpha4beta7. Binding to the integrin is influenced by glycosylation patterns on gp120 that are consistent with the signature of transmission-linked viral isolates. In light of these findings, we hypothesize that the ability of HIV-1 gp120 to bind alpha4beta7 may confer increased transmission fitness. In this regard, the delineation of the role of alpha4beta7 in HIV pathogenesis provides critical new information for understanding the basic mechanisms underlying HIV-mediated immune dysfunction and HIV transmission.